Method of treating weight loss disorders

ABSTRACT

There is disclosed a method of treating weight loss disorders. This method consists essentially of administering to a mammal, such as a human, a daily dosage of at least about 10 milligrams per 37 kilogram body weight of at least one opiate antagonist. These opiate antagonists include naloxone, naltrexone, nalorphine, diprenorphine, levallorphan, pentazocine, metazocine, cyclozocine, etazocine, and pharmacologically acceptable salts thereof. The use of naloxone hydrochloride as the opiate antagonist is preferred.

BACKGROUND OF THE INVENTION

This invention relates generally to the use of narcotic antagonists,including naloxone and naltrexone, to counteract the physiologicaland/or psychological effects of starvation by food and fluid deprivationin animals, including humans. In particular, this invention relates to amethod for treating mammals, including humans, with opiate antagonistsin order to alleviate weight loss disorders, including anorexia nervosaand bulimia.

Deprivation of food and fluids leading to starvation with accompanyingweight loss may be imposed by "circumstances", as, for example, famine,or by others, as, for example, a prisoner of war situation. It may alsobe self imposed, as in the case of anorexia nervosa and bulimia.

The term "anorexia" refers to a medical symptom indicating a lack orloss of appetite for food (see Dorland's Medical Dictionary, 25th Ed.)which may occur in a variety of medical conditions and diseases. Incontrast, the term "anorexia nervosa" denotes a diagnosis of a severenervous condition characterized by a relentless addiction-like pursuitof thinness to the point of cachexia by voluntarily withholding foodsand fluids, and, at times, by excessive exercising, that results fromdieting to achieve a socially pleasing slim appearance.

Anorexia nervosa is also associated with physiological changes thatinclude abnormal endocrine and metabolic functions, variations fromnormal urine concentrations, and a lowering of body temperature,respiratory, and cardiovascular functions. These changes appear to bepart of a universal adaptive mechanism of starvation since they arereversible with weight gain and do not differ substantially from thosefound in other forms of starvation, such as famine or prisoner of warsituations.

Bulimia is characterized by excessive intake of food and fluids followedby, or associated with, purgatory maneuvers designed to rid oneself ofthe ingested food and fluids. Such purgatory self-manipulations include,but may not be restricted to vomiting, use of laxatives and rectalenemas, and depletion of body fluids by diuretic agents. Each of thesemethods leads to body fluid loss and disturbance of the body'selectrolyte balance. Excessive food intake and purging behavior usuallyresults from excessive dieting and can become an addictive compulsivehabit, especially in distressed and depressed individuals.

Opiate antagonists are synthetic compounds which may be given to optiateaddicts to block the physical and/or psychological effects of opiates.These optiate antagonists include naltrexone and naloxone.

Naloxone is a powerful antagonist of exogenous opiates and naturallyoccurring opioid peptide hormones which have opiate like effects on theorganism. It is a relatively pure opiate antagonist and is administeredintravenously. Naltrexone is known to be a powerful antagonist ofexogenous opiates and naturally occurring opioid peptide hormones whichhave opiate like effects on the organism. It may be prepared inaccordance with the teachings of U.S. Pat. No. 3,322,950 and CanadianPat. No. 913,077. Naltrexone is a relatively pure opiate antagonist andis effective when given orally.

Naltrexone has been used in the past to induce anorexia as discussed inU.S. Pat. No. 4,217,353. In that patent, there is discussed certainstudies directed principally to the safety and efficacy of naltrexone asan oral narcotic antagonist. In these studies, the patentee notes thatthere are some isolated and contradictory statements concerning theeffect of naltrexone on appetite in man.

One study has suggested the use of naloxone in treating anorexianervosa. See Moore et al "Naloxone in the Treatment of Anorexia Nervosa:Effect on Weight Gain and Lipolysis", 74 J. Roy. Soc. Med. 129 (1981).This study of the effect of naloxone on anorexics is inconclusive,however, because the naloxone treatment was coupled with hypercaloricfeeding (3000-4000 kcal dietary intake) as well as the administration ofantidepressant medication (usually amitriptylene). A letter in that samepublication suggests that the weight gain described in the Moore et alstudy might be related to interference with vomiting, both voluntary andinvoluntary. It also discusses a possible role of opiate antagonists inthe therapy of anorexia nervosa. 74 J. Roy. Soc. Med. 631. The"vomiting" explanation was subsequently discussed and dismissed by aco-author of the Moore et al article. 74 J. Roy. Soc. Med. 945.

The search has continued for improved methods of treating weight lossdisorders such as anorexia nervosa and bulimia. This invention was madeas a result of that search.

OBJECTS AND SUMMARY OF THE INVENTION

Accordingly, it is a general object of the present invention to avoid orsubstantially alleviate the above-discussed problems of the prior art.

A more specific object of the present invention is to provide a methodfor treating weight loss disorders wherein the physiological and/orbehavioral changes which result from these disorders are reversed andthe patient is not subjected to harmful side effects.

A further object of the present invention is to provide for weight gainin a patient afflicted with anorexia nervosa.

Another object of the present invention is to eliminate theself-destructive excessive food intake and purging behavior in patientsafflicted with bulimia, which leads to loss of body fluids andelectrolyte imbalance.

Still other objects and advantages of the present invention will becomeapparent from the following summary of the invention and description ofits preferred embodiments.

The present invention provides a method of treating weight lossdisorders. This method comprises administering to a mammal, such as ahuman, a daily dosage of at least about ten milligrams per 37 kilogrambody weight of an opiate antagonist. The opiate antagonist may benaloxone, naltrexone, nalorphine, diprenorphine, levallorphan,pentazocine, metazocine, cyclozocine, etazocine, or pharmacologicallyacceptable salts thereof. Mixtures of two or more opiate antogonists mayalso be used.

The present invention is based, in part, on the discovery that prolongedstarvation triggers a physical and mental adaptive mechanism that ismediated by endogenous opioid peptides or endorphins. Increasedpreoccupation with food as well as a reduction of the body metabolismand a numbing of the pyschological effects of starvation appear to bethe essential features of this mechanism. Consistent with thesefeatures, anorexia nervosa is not associated with a loss of appetite, asearlier thought, but is characterized by an increasing preoccupationwith food and intensified food related activities including a powerfulurge to eat as dieting progresses. This urge is resisted by anorexicsfor the sake of benefitting from the sense of well-being mediated byelevated levels of endorphins.

Endorphins are powerful enforcers which produce tolerance and dependenceby mediating cellular mechanisms of addiction. In sufficientconcentration, they provide a sense of well-being. Most anorexicsinitiate a starvation diet to counteract a sense of distress and/ordepression. This sense of well-being provided by the endorphins makesanorexics susceptible to the addictive effects of the endorphins. Oncethe addictive mechanism is initiated, the need to overcome tolerance tothe reinforcing effects of the endorphins causes the anorexic to seekprogressively lower weight which, absent intervention such as by themethod of the present invention, can ultimately lead to death.

The present invention is also based, in part, on the discovery thatendogenous opioid peptides are triggered by the purgatory acts performedby bulimics. These peptides are the reinforcing substrate whichmotivates and perpetuates bulimic behavior consistent with the patternof addiction.

Opiate antagonists, such as naloxone and naltrexone, act as powerfulantagonists of endogenous opiates and naturally occurring opioid peptidehormones by blocking the receptor sites, and thus the euphoria-producingeffects, of opiates. Once self-starvation no longer "feels good", as aresult of this blockage, the patient may be induced to follow aprescribed diet which, in combination with appropriate psychotherapy,will enable weight gain and the correction of physiological and/orbehavioral problems associated with the weight loss disorder.

The use of minor amounts of opiate antagonists will not effectivelycounteract the effects, including the addictive effects, of theendorphins. While the use of minor amounts of opiate antagonists, suchas the amounts disclosed in the above-discussed Moore et al article, mayhave an effect vis-a-vis lipolysis, such amounts are substantiallyineffective to counteract the addictive and other effects of theendorphins.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As noted above, the present invention is directed to a method oftreating weight loss disorders such as anorexia nervosa and bulimia. Themethod consists essentially of administering to a mammal, such as ahuman, a daily dosage of generally at least about 10, typically fromabout 30 to about 200, and preferably from about 50 to about 150milligrams of an opiate antagonist based upon a 37 kilogram body weight.

These opiate antagonists include naloxone, naltrexone, nalorphine,diprenorphine, levallorphan, pentazocine, metazocine, cyclozocine,etazocine, and pharmacologically acceptable salts thereof. Mixtures oftwo or more opiate antagonists may also be used.

These opiate antagonists are described above in terms of their commonnames. They may also be described in terms of their chemical names.Naloxone, for example, is also known as N-allylnoroxymorphone;naltrexone is(-)-17-(cyclopropylmethyl)-4,5,alpha-epoxy-3,14-dihydroxymorphinan-6-one;nalorphine is the alkyl derivative of morphine, i.e., N-allynormorphine;levallorphan is 1-N-allyl-3-hydroxynorphinan; and pentazocine is2-dimethylallyl-5,9-dimethyl-2'-hydroxy-benzomorphan.

Naloxone, naltrexone and/or their pharmacologically acceptable salts arepreferred for use in the present invention. Naloxone and itspharmacologically acceptable salts are administered intravenouslywhereas naltrexone and its pharmacologically acceptable salts areadministered orally. Naloxone hydrochloride is particularly preferred.

The opiate antagonist is administered either orally or intravenously fora time sufficient to allow the patient's weight to increase and to breakthe addictive effect of the opiates. This time period may vary widelyand is dependent upon the circumstances in a particular case.

This invention is further illustrated by the following Examples.

EXAMPLES

Nine female hospitalized adolescents, who fulfill the ResearchDiagnostic Criteria for anorexia nervosa, as described in Feighner et alin "Diagnostic Criteria For Use In Psychiatric Research", 26 Arch. Gen.Psychiatry 57 (1972), and who have a body weight of approximately 37kilograms, are treated with naloxone, naltrexone, and placebo drugscommercially available from DuPont Pharmaceuticals, Inc. Naloxonehydrochloride is dissolved in sufficient normal saline solution to beinfused over a four hour period. Four different dosages (0.2; 0.4; 0.8;and 1.2 milligrams per kilogram of body weight) are administered over afour hour period to each patient in the study. One four houradministration is provided on every other day. Each day of naloxonetreatment is followed by a day of placebo treatment in a double blindarrangement comprising a four hour intravenous infusion of a placeboconsisting of the inert ingredients of naloxone hydrochloride dissolvedin normal saline solution.

Naltrexone is orally administered to one patient having a body weight ofapproximately 32 kilograms in four increasing daily dosages of 25, 50,75, and 100 milligrams with each of the dosages matched by a placebo onalternate days in double blind fashion.

The hormone levels measured in these subjects show less response toendorphin receptor blockade by naloxone than the response of the samehormones to naloxone administration in normal healthy volunteers.Furthermore, several behavioral observations made on days of opiateantagonist administration suggest a powerful effect of endorphins on theregulation of coping, mood, and eating behavior. Only for the durationof the pharmacological action of naloxone these subjects displayed amarked change. The well-known hypervigilant, manipulative, irritable,restless, reticent and angry behavior changed for about 12-24 hours intoa state of quiet, tearful weeping for no apparent reason, of wishingsomeone close for comfort and sharing of worried thoughts, and ofapparent defenselessness. Furthermore, the usual avoidance of food andanxiety related to a fear of obesity gave way to one of quietlyaccepting the prescribed diet and enlisting encouragement from staff.These changes occur under opiate antagonist, but not placebo,administration. Also, these changes are more apparent with increasingopiate antagonist dosage.

The principles, preferred embodiments, and modes of operation of theinvention have been described in the foregoing specification. Theinvention which is intended to be protected herein, however, is not tobe construed as limited to the particular forms disclosed, since theseare to be regarded as illustrative rather than restrictive. Variationsand changes may be made by those skilled in the art without departingfrom the spirit of the invention.

I claim:
 1. A method of treating weight loss disorders consistingessentially of administering to a human having a weight loss disorder adaily dosage of an effective amount which consists essentially of atleast about 10 milligrams per 37 kilogram body weight of at least oneopiate antagonist selected from the group consisting of naloxone,naltrexone, nalorphine, diprenorphine, levallorphan, pentazocine,metazocine, cyclozocine, etazocine, and pharmacologically acceptablesalts thereof.
 2. The method of claim 1 wherein said mammal is a human.3. The method of claim 2 wherein said opiate antagonist is naloxone or apharmacologically acceptable salt thereof.
 4. The method of claim 2wherein said opiate antagonist is naltrexone or a pharmacologicallyacceptable salt thereof.
 5. The method of claim 3 wherein said naloxoneor said pharmacologically acceptable salt thereof is administeredintravenously.
 6. The method of claim 5 wherein said daily dosage isfrom about 30 to about 200 milligrams per 37 kilogram body weight. 7.The method of claim 3 wherein said pharmacologically acceptable salt isnaloxone hydrochloride.
 8. The method of claim 4 wherein said naltrexoneor said pharmacologically acceptable salt thereof is administeredorally.
 9. The method of claim 8 wherein said daily dosage is from about30 to about 200 milligrams per 37 kilogram body weight.
 10. The methodof claim 1 wherein said daily dosage is from about 30 to about 200milligrams per 37 kilogram body weight and said opiate antagonist isselected from the group consisting of naloxone, naltrexone, andpharmacologically acceptable salts thereof.
 11. A method of treatingweight loss disorders consisting essentially of administering to a humanhaving a weight loss disorder a daily dosage which consists essentiallyof from about 50 to about 150 milligrams per 37 kilogram body weight ofnaloxone hydrochloride.